Alterations in cell cycle events that disrupt neuronal production are likely to underlie cortical malformations[unreadable] associated with microcephaly. This project examines the dynamics of proliferation in the embryonic[unreadable] telencephalon in normal and mutant mice to gain insights into mechanisms that regulate neurogenesis in[unreadable] health and disease. Specific subsets of neocortical neurons arise from spatially distributed proliferative[unreadable] zones and involve distinct molecular signals. Most cortical inhibitory interneurons originate in the subcortical[unreadable] telencephalon, while excitatory projection neurons arise in the cortical telencephalon. These cell types[unreadable] converge in the developing neocortex to form characteristic cortical circuits. The experiments outlined in this[unreadable] proposal will examine how patterns of neurogenesis differ between the cortical and subcortical telencephalon[unreadable] and within the two neurogenic niches, the ventricular (VZ) and subventricular (SVZ) zones. We will explore[unreadable] how neurogenesis may be modulated by intrinsic and epigenetic factors within these regions and how[unreadable] regional alterations in the pattern of division might contribute to microcephaly.[unreadable] We will use techniques of retroviral lineage analysis, optical imaging, time-lapse confocal microscopy, and[unreadable] electrophysiology to characterize progenitor divisions and answer the following questions: How do patterns[unreadable] of asymmetric and symmetric progenitor cell divisions generate neuronal diversity in the developing[unreadable] subcortical telencephalon? Do spatially distinct neurogenic niches determine the mode of cell division and[unreadable] patterns of neurogenesis? Does cleavage plane determine or predict progenitor fate? Do cell-extrinsic, fate[unreadable] determining signals such as GABA activate cortical VZ cells and promote symmetric progenitor divisions? Do[unreadable] regulators of cell cycle progression such as cyclin D2 influence cell cycle dynamics by promoting neurogenic[unreadable] division? Does the secreted fate-influencing factor Sonic Hedgehog regulate neurogenesis in the subcortical[unreadable] VZ and SVZ? The critical balance between excitation and inhibition underlies the regulation of excitability in[unreadable] the developing and mature cortex, and an imbalance can have significant pathological effects ranging from[unreadable] subtle disorders associated with seizures, to devastating cortical malformations with intractable epilepsy.[unreadable] The data from these experiments will help us to understand how this critical balance is maintained.